An antibiotic from an uncultured bacterium binds to an immutable target

作者：Rhythm Shukla, Aaron J. Peoples, Kevin Christopher Ludwig, Sourav Maity, Maik G. N. Derks, Stefania De Benedetti, Annika M. Krueger, Bram J. A. Vermeulen, Theresa Anisja Harbig, Francesca Lavore, Raj Kumar, Rodrigo V. Honorato, Fabian Grein, Kay Nieselt, Yangping Liu, Alexandre M. J. J. Bonvin, Marc Baldus, Ulrich Kubitscheck, Eefjan J. Breukink, Catherine Achorn, Anthony G. Nitti, Christopher J. Schwalen, Amy L. Spoering, Losee Lucy Ling, Dallas E. Hughes, Moreno Lelli, Wouter H. Roos, Kim Lewis, Tanja Schneider, Markus H. Weingarth · 发表于：Cell · 年份：2023 · DOI：10.1016/j.cell.2023.07.038 · 被引用次数：144 · 研究领域：Genomics and Phylogenetic Studies、Bacteriophages and microbial interactions、Bacterial Genetics and Biotechnology

Antimicrobial resistance is a leading mortality factor worldwide. Here, we report the discovery of clovibactin, an antibiotic isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positive bacterial pathogens without detectable resistance. Using biochemical assays, solid-state nuclear magnetic resonance, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C 55 PP, lipid II, and lipid III WTA ). Clovibactin uses an unusual hydrophobic interface to tightly wrap around pyrophosphate but bypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups. This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development.